Increased REST to optimize lifespan?

Increased REST to optimize lifespan?

Publication date: Nov 24, 2019

Reduced levels of neural activity are associated with a longer lifespan in the nematode C. elegans and in mice. Augmented neural activity is associated with a shorter lifespan. Recent studies show that levels of repressor element 1-silencing transcription factor (REST), increases with normal aging in mice and humans, and reduces neuronal excitation. In C. elegans, increased expression of spr-4, a functional REST homologue, increased the worm lifespan and is required for classical lifespan increase mediated by reduced DAF2/insulin-IGF-1 and increased DAF16. Preliminary evidence shows that REST and FOXO1, a DAF16, homolog increase during mammalian aging, and that REST activity is needed for the age-related FOXO1 increase. On the other hand, REST is activated in epilepsy and plays a role in the pathogenesis of Huntington’s disease. A simple unifying hypothesis suggests that REST is a “goldilocks-effect factor”: too little REST promotes excitotoxic activity, which in turn leads to neurodegenerative diseases like Alzheimer’s. Appropriate increased levels of REST maintain excitation-inhibition (E-I) balance by reducing potential excitotoxic activity. Increased levels of REST beyond this is toxic as neurons become dysfunctional due to loss of a neuronal phenotype.

Larrick, J. and Mendelsohn, A.R. Increased REST to optimize lifespan? 06795. 2019 Rejuvenation Res.

Concepts Keywords
Aging Epilepsy
Alzheimer Disease
Epilepsy Branches of biology
Excitotoxic Ageing
Goldilocks Old age
Homolog Forkhead transcription factors
Homologue Gerontology
Huntington Senescence
Insulin MTOR
Mice Daf-16
Nematode FOXO1
Neurodegenerative Diseases RE1-silencing transcription factor
Transcription Factor


Type Source Name
disease MESH aging
drug DRUGBANK Mecasermin
disease MESH epilepsy
disease MESH neurodegenerative diseases
drug DRUGBANK Isoxaflutole


Original Article

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